An early event in the development of atherosclerotic lesions is the accumulation of lipid by subendothelial macrophages known as "foam cells". The foam cells are characterized by an increased number of lipoprotein receptors and/or an enhanced ability to internalize lipoproteins and/or lipids. To inhibit artheroschlerotic lesion formation, research has been directed to the identification of receptors which mediate foam cell generation in vivo. To this end, various forms of modified low density lipoproteins ("LDLs"), including acetylated LDL ("acLDL") (Goldstein et al., Proc. Natl. Acad. Sci. USA 76:333-337 (1979)) and oxidized LDL ("oxLDL") (Steinbrecher et al., Proc. Natl. Acad. Sci. USA 81:3883-3887 (1984); and Henriksen et al., Proc. Natl. Acad. Sci. USA 78:6499-6503 (1981)) have been prepared and tested for their ability to increase LDL particle uptake by macrophages in vitro.
A macrophage receptor which mediates acLDL uptake has been purified and the gene encoding this protein (also known as the "scavenger receptor") has been cloned (Kodama et al., Nature 343:531-535 (1990)). In contrast to the LDL receptor (which does not recognize acLDL), expression of the scavenger receptor is not down-regulated by high levels of intracellular cholesterol (Goldstein, J. L., et al., Proc. Natl. Acad. Sci. USA 76:333-337 (1979)).
In addition to acLDL, oxidized LDL ("oxLDL") has been shown to selectively bind to the acLDL receptor (Henriksen et al., Proc. Natl. Acad. Sci. USA 78:6499-6503 (1981)). Since acLDL has not been detected in situ or in vivo, oxLDL appears to be the physiologic ligand for this receptor (Stanton, L., et al., supra.). Thus, the binding of oxLDL to the acLDL receptor appears to contribute to macrophage lipid loading in vivo.
A recent study of the uptake of oxLDL by macrophages and by transfected 293 cells expressing the mouse acLDL receptor, suggests that an additional receptor ("FcgammaRII-B2"), known to mediate immune complex uptake via recognition of the Fc region of IgG, also serves as an additional high affinity receptor for oxLDL. Whether lipoprotein internalization via the Fc receptor leads to foam cell formation has not been addressed in the literature.
In view of the high specificity of the above-identified receptors, various attempts have been made in the prior art to utilize these receptors for delivering a drug to a macrophage in vivo. (See e.g., U.S. Pat. No. 5,192,264; Nicolas, J., et al., Annals of Tropical Med. and Parasitology 83(4):325-336 (1990)). In general, these therapeutic methods have in common the administration of a lipophilic drug to a patient's bloodstream, followed by internalization of the drug by the macrophage in vivo.